Despite the slowly declining incidence of global HIV infections in recent years, the HIV/AIDS epidemic causes over 2 million new infections every year, representing one of the leading causes of infection-related deaths worldwide. Because an effective HIV vaccine remains elusive and the majority of new infections occur in the developing countries, there is thus an urgent need for safe, effective, and inexpensive pre-exposure prophylaxis (PrEP) modalities for preventing viral mucosal transmission, such as topical microbicides. Currently, most efforts in microbicide development are focused on small-molecule antiretrovirals (ARVs) that have been developed to treat HIV-infected individuals. This paradigm has emerged since the seminal report published in 2010 on the CAPRISA 004 Phase IIb clinical trial, showing that peri-coital use of a gel containing the reverse-transcriptase (RT) inhibitor tenofovir (TFV) provided modest yet significant protection. Clinical development of ARVs for PrEP can be greatly facilitated by available safety and efficacy information from their therapeutic use. However, it is desirable to expand microbicide candidates to non-ARV-based HIV inhibitors because of concerns for the PrEP/microbicide use of ARVs. For example, potential conflict of priorities between treatment and prevention may arise, and emergence of escape mutants could compromise available therapy options. Human anti-HIV-1 broadly neutralizing monoclonal antibodies (bnMAbs) may provide attractive options in this context, given their proven protective efficacy against infection upon pre- and/or post-exposure uses in animal challenge models and inherent general safety because of their human origin. A Phase I randomized controlled clinical trial has been recently completed for a vaginal microbicide candidate containing three bnMAbs 2F5, 4E10, and 2G12, showing that daily vaginal administration of the bnMAbs (50 mg each) to healthy women for 12 days was safe and well tolerated.
VRC01 is a CD4-binding site (CD4bs)-specific bnMAb recently isolated from a slowly progressing HIV-1 infected donor. It has remarkable neutralization coverage compared to most other HIV-1-neutralizing MAbs reported to date; about 90% of genetically diverse heterologous HIV-1 strains have been neutralized with 50% inhibitory concentrations (IC50) at less than 1 μg/ml in in vitro HIV-1 neutralization assays. Transmitted/founder viruses of A, B, and C clades were shown to be susceptible to VRC01 neutralization. Veselinovic, et al. recently reported that a topical gel formulation of VRC01 protected against vaginal challenge with the chemokine receptor CCR5-using HIV-1 BaL in a humanized mouse model. Collectively, these findings suggest that VRC01 and other similar bnMAbs constitute promising non-ARV anti-HIV-1 molecules as topical microbicide candidates, justifying further preclinical investigation to determine their feasibility.
Notwithstanding the remarkable breadth and potency of VRC01's anti-HIV-1 activity, the existence of VRC01-resistant viruses has been demonstrated in the VRC01 donor and in other broadly neutralizing plasma donors. A recent passive immunotherapy study using a humanized mouse model has shown that a monotherapeutic use of the VRC01-like CD4bs-specific bnMAb NIH45-46G54W failed to control viremia and the emergence of resistant viruses, although combination with four other bnMAbs rendered complete protection. These findings suggest that a single component microbicide based on VRC01 or any other bnMAb may fail to provide sufficient protection and could even lead to the accumulation of resistant strains in circulating virus populations. In practice, a combinatorial strategy will have to be implemented to any microbicide candidates, as has been the case in the treatment of HIV-1-infected patients. Thus, analysis of VRC01's potential for synergy with other microbicide candidates would provide valuable information towards the bnMAb's potential as a component of combination microbicides.
While efficacy and safety are critical aspects in pharmaceutical development, it is also important that microbicide candidates are economically viable. Indeed, this is perhaps the most significant challenge for MAbs, as the current mammalian cell culture-based production system will be difficult to provide the proteins at a cost and scale required for global HIV-1 prevention. Accordingly, a method of producing antibodies, such as anti-HIV VRC01 antibodies, that allows the antibodies to be produced at a high level and in an economical manner would be both highly desirable and beneficial.